Tumor growth is angiogenesis dependent and tumors normally subvert developmental signaling programs. We study blood vessel development using zebrafish as a model system. Some of the clues for vessel development are beginning to emerge from nerves. Stereotypical patterns of vascular and neuronal networks suggest that specific genetic programs tightly control path determination and consequently angiogenesis and axon guidance mechanisms. Recently, description of cell surface molecules that are shared by neuronal and endothelial cells has suggested that this association may be more prevalent than previously thought. Neuropilins, ephrins, and plexins are a few examples that are implicated in both processes. Recently, roundabouts (Robo), a class of neural guidance receptors that bind slit ligands have joined this group. In vertebrate systems, three Robo receptor family members were identified, all with prominent neural expression. More recently, a fourth member of the Robo receptor family, robo4 was identified in a bioinformatics screen for novel transcripts in endothelial versus non-endothelial SAGE libraries. Robo4 is predominantly expressed in tumor vessels and to investigate function of this molecule we studied its ortholog in zebrafish. Robo4 shows a transient intersomitic vessel expression during embryonic vascular development. Using gene knockdown and overexpression approaches we have demonstrated that robo4 is essential for angiogenesis in vivo. Currently, studies are underway to investigate the mechanisms by which Robo4 guides endothelial cells to their target.